Phosphatase activation as therapeutic strategy for Chronic lymphocyic leukemia

磷酸酶激活作为慢性淋巴细胞白血病的治疗策略

• 批准号: 9767716
• 负责人: Natarajan Muthusamy
• 金额: $ 42.45万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767716
• 关键词: Acute Lymphocytic Leukemia; Animal Model; Antigens; Apoptosis; Apoptotic; B lymphoid malignancy; B-Lymphocytes; BCL2 gene; Bone Marrow; Cell Death; Cell Nucleus; Cellular biology; Chronic; Chronic Lymphocytic Leukemia; Chronic Myeloid Leukemia; Clinical Trials; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Elderly; Emu species; Enzymes; FDA approved; Family; Formulation; Goals; Hematologic Neoplasms; Hematology; Heme; Human; Immuno-Chemotherapy; Immunosuppressive Agents; In Vitro; Individual; Investigation; Lead; Legal patent; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Modeling; Mus; NR0B2 gene; New Agents; Normal Cell; Normal tissue morphology; Nuclear; Patients; Pharmaceutical Chemistry; Pharmacodynamics; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Progression-Free Survivals; Property; Protein phosphatase; Proteins; Proteomics; ROR1 gene; Recurrence; Regimen; Regulation; Relapse; Resistance; Role; Spleen; Testing; Therapeutic; Therapeutic Index; Tissues; Treatment Efficacy; Tumor Antigens; Western World; Work; cancer cell; chronic lymphocytic leukemia cell; clinical application; clinical development; cytotoxic; cytotoxicity; design; drug development; drug disposition; efficacy study; in vivo; in vivo evaluation; leukemia; model design; models and simulation; mouse model; neoplastic cell; novel; novel therapeutics; off-patent; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; preclinical evaluation; protein activation; public health relevance; targeted agent; targeted delivery; translational medicine

 DESCRIPTION (provided by applicant): Despite prolonged progression free survival with the introduction of novel therapies for Chronic lymphocytic leukemia (CLL) currently available therapies are not curative in all patients and patients who relapse generally respond poorly. Identification of new agents that work in resistant patients represents a major focus of investigation. Constitutive phosphorylation of proteins associated with prolonged survival and defective apoptosis is a recurrent theme in CLL and other cancers. While inhibition of kinases is actively pursued, pharmacological activation of protein phosphatases is less explored and represents a paradigm shift for potential therapeutic modulation of aberrantly phosphorylated proteins in CLL. We have identified FTY720, an FDA approved immunosuppressant, to mediate cytotoxicity through a protein phosphatase 2A (PP2A) activation dependent mechanism in CLL. Despite its potent pre-clinical activity in multiple heme-malignancies including CLL, mantle cell lymphoma, chronic myeloid leukemia and acute lymphoid leukemia, the immunosuppressive property of FTY720 precluded its further development for clinical application in heme-malignancies. We therefore developed a non-immunosuppressive FTY720 derivative, OSU-2S, with potent cytotoxic activity. This proposal will pursue mechanistic, pharmacological and translational development of OSU-2S in B cell malignancies. Specifically, in Aim 1 we propose to identify the direct target of OSU-2S and determine the mechanistic basis of OSU-2S induced apoptosis with emphasis on phosphatases in CLL. To overcome potential off target effects of OSU-2S in-vivo, we generated CLL tumor antigen (ROR1) targeted immunoliposomal delivery formulations (2A2-OSU-2S-ILP) and CLL mouse models expressing human ROR1 antigen on leukemic B cells. In Aim 2, we propose to maximize the therapeutic index of 2A2-OSU-2S-ILP by a) determining maximum tolerable doses and exposures of 2A2-OSU-2S-ILP in human ROR1+Tcl1 CLL mice; b) characterizing the in-vivo relationships between 2A2-OSU-2S-ILP pharmacokinetics and pharmacodynamic (PK/PD) modulation of pSHP1 in bone marrow, spleen, circulating WBCs and other tissues in Eµ-ROR1-Tcl1 mice, and c) using PK/PD modeling and simulation to design optimal dose regimens of 2A2-OSU-2S-ILP that maximize pSHP1 induction while minimizing dose levels and OSU-2S exposure in non-diseased tissues. We will validate the in-vivo therapeutic efficacy of the human ROR1 targeted OSU-2S formulations in our human ROR1+ CLL mouse model in Aim 3. At completion of this project we will have generated sufficient mechanistic and pharmacological data with OSU-2S to justify its transition to early clinical trials for CLL. We are poised to accomplish this through our patented OSU-2S, novel CLL targeted delivery formulation and unique animal models exclusively developed to meet our needs to perform a comprehensive pre-clinical evaluation. To accomplish this goal we have assembled a highly interactive team with expertise in proteomics, translational medicine, drug development, mouse modeling, drug delivery, and PK/PD modeling and simulation.

 描述（由适用提供）：尽管慢性淋巴细胞性白血病（CLL）引入了当前可用的疗法的新型疗法，但在所有患者中，中继的患者和继电器通常反应较差的患者并非目前可用的疗法。鉴定在抵抗患者中工作的新代理人是投资的主要重点。与长期生存和缺陷凋亡相关的蛋白质的组成型磷酸化是CLL和其他癌症的复发主题。虽然对激酶的抑制作用是积极追求的，但探索蛋白磷酸酶的药物激活较少，代表了CLL中异常磷酸化蛋白的潜在治疗调节的范式转移。我们已经确定了FDA批准的免疫抑制剂FTY720，通过CLL中的蛋白质磷酸酶2a（PP2A）激活机制介导细胞毒性。尽管在包括CLL，披风细胞淋巴瘤，慢性骨髓性白血病和急性淋巴白血病在内的多种血红素疗程中具有潜在的临床前活性，但FTY720的免疫抑制性能阻止了其在血脂中临床应用的进一步发展。因此，我们开发了具有潜在的细胞毒性活性的非免疫抑制FTY720衍生物OSU-2S。该提案将追求B细胞恶性肿瘤中OSU-2的机械，药物和翻译发展。具体而言，在AIM 1中，我们建议识别OSU-2S的直接靶标，并确定OSU-2S诱导的凋亡的机理基础，重点是CLL中的磷酸酶。为了克服OSU-2S中的潜在靶向影响，我们产生了CLL肿瘤抗原（ROR1）靶向免疫脂质体递送配方（2A2-OSU-2S-ILP）和表达人类ROR1抗原在白血病B细胞上的CLL小鼠模型。在AIM 2中，我们建议通过a）确定在人ROR1+TCL1 CLL小鼠中确定2A2-OSU-2S-ILP的最大耐受剂量和暴露的最大耐受剂量和暴露； b）表征2A2-OSU-2S-2S-ILP药代动力学和药效学（PK/PD）在骨髓，shleen，sleen，循环WBC和其他时机和其他时机中的PSHP1调节中的PSHP1，以及使用PK/PD建模的e µ-ror1-tcl1小鼠中的其他时间，以及使用PK/PD建模型 - 2A-最大化PSHP1诱导，同时最大程度地减少非剂量组织的剂量水平和OSU-2S暴露。我们将在AIM 3中验证人ROR1靶向OSU-2S公式的体内治疗效率。在完成该项目时，我们将使用OSU-2S生成足够的机械和药物数据，以证明其对CLL的早期临床试验的过渡。通过获得专利的OSU-2，新颖的CLL靶向输送公式和独特的动物模型，我们被毒死了，以满足我们进行全面的临床前评估的需求。为了实现这一目标，我们组装了一个高度互动的团队，具有蛋白质组学，翻译医学，药物开发，小鼠建模，药物输送以及PK/PD建模和仿真方面的专业知识。

项目成果

Polo-like kinase inhibitor volasertib marginally enhances the efficacy of the novel Fc-engineered anti-CD33 antibody BI 836858 in acute myeloid leukemia.

• DOI: 10.18632/oncotarget.23880
• 发表时间: 2018-02-09
• 期刊: Oncotarget
• 作者: Gopalakrishnan B;Cheney C;Mani R;Mo X;Bucci D;Walker A;Klisovic R;Bhatnagar B;Walsh K;Rueter B;Waizenegger IC;Heider KH;Blum W;Vasu S;Muthusamy N
• 通讯作者: Muthusamy N